The main objective of this research proposal is to understand the pathogenesis of some important pulmonary complications associated with HIV infection, using a murine model of these diseases, the CD4C/HIV Tg mice. These Tg mice express some of the gene products of HIV-1 in cells normally targeted by HIV-1 infection in humans, namely CD4+ CD8+ immature and CD4+ CD8- mature T cells and cells of the dendritic/macrophage lineage. The lung diseases observed in these Tg mice mimic the lung pathologies described in individuals with AIDS. Because these pathological lung lesions are associated with many other phenotypes very similar to those found in humans infected with HIV-1, we postulate that these Tg mice are relevant to human AIDS and that they constitute a very good model for the lung diseases associated with HIV-1 in humans. To understand the pathogenesis of this lung disease, we intend: AIM 1- To determine whether the development of the lung disease of CD4C/HIV Tg mice is caused by expression of HIV-1 Nef in cells of the immune system or in other cells. AIM 2- To identify the Nef-expressing cells required to induce lung disease in CD4C/HIV Tg mice. AIM 3- To determine, using an inducible trangene, whether the development of the lung disease in CD4C/HIV Tg mice occurs also when Nef is expressed later in life, in adulthood. AIIM 4- To map and identify the gene(s) responsible for the enhanced susceptibility of some strains of mice to the development of LIP in CD4C/HIV Tg mice. AIM 5- To determine whether there is a genetic basis for the development of sarcoidosis and pulmonary hypertension in CD4C/HIV Tg mice. This research is especially relevant to public health, especially children with AIDS, developing lung diseases at high frequency.